Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene
Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we perfor...
| Main Authors: | , , |
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| Format: | Journal Article |
| Language: | English |
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2023
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| Online Access: | https://hdl.handle.net/10356/165636 |
| _version_ | 1811687933018636288 |
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| author | Boehm, Bernhard Otto Kratzer, Wolfgang Bansal, Vikas |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Boehm, Bernhard Otto Kratzer, Wolfgang Bansal, Vikas |
| author_sort | Boehm, Bernhard Otto |
| collection | NTU |
| description | Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities. |
| first_indexed | 2024-10-01T05:24:11Z |
| format | Journal Article |
| id | ntu-10356/165636 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:24:11Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1656362023-04-09T15:37:42Z Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene Boehm, Bernhard Otto Kratzer, Wolfgang Bansal, Vikas Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Transcription Factor PAX6 Diabetic Neuropathy Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities. Nanyang Technological University Published version This project was supported by start-up funds from the Department of Pediatrics at University of California San Diego. BOB is supported by an Ong Tiong Tat Professorship from the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore. 2023-04-05T03:01:16Z 2023-04-05T03:01:16Z 2023 Journal Article Boehm, B. O., Kratzer, W. & Bansal, V. (2023). Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene. European Journal of Human Genetics, 31(1), 89-96. https://dx.doi.org/10.1038/s41431-022-01182-y 1018-4813 https://hdl.handle.net/10356/165636 10.1038/s41431-022-01182-y 36202929 2-s2.0-85139516900 1 31 89 96 en European Journal of Human Genetics © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Science::Medicine Transcription Factor PAX6 Diabetic Neuropathy Boehm, Bernhard Otto Kratzer, Wolfgang Bansal, Vikas Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title | Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title_full | Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title_fullStr | Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title_full_unstemmed | Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title_short | Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene |
| title_sort | whole genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the pax6 gene |
| topic | Science::Medicine Transcription Factor PAX6 Diabetic Neuropathy |
| url | https://hdl.handle.net/10356/165636 |
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